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Compelling Indications Should be Listed for Individual Beta-Blockers (Due to

Diversity), Not for the Whole Class

Article in Current Vascular Pharmacology · May 2020

DOI: 10.2174/1570161118666200518113833

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Letter to the Editor Current Vascular Pharmacology, 2021, Vol. 19, No. 00 1

LETTER TO THE EDITOR

Compelling Indications Should be Listed for Individual Beta-Blockers

(Due to Diversity), Not for the Whole Class

Goran Koracevic1,2, Sladjana Micic2, Milovan Stojanovic3,*, Dragan Lovic4, Dragan Simic5, Mirko Colic6,
Maja Koracevic2,7, Aleksandar Stojkovic1 and Milenko Paunovic8

ARTICLE HISTORY
Received: January 25, 2020
Revised: May 15, 2020
Accepted: May 06, 2020
DOI:
10.2174/1570161118666200518113833
¹Department for Cardiovascular Diseases, Clinical Center Nis, Serbia; ²Faculty of Medicine,
University of Nis, Serbia; 3Institute for Treatment and Rehabilitation Niska Banja, Nis, Ser-
bia; 4Clinic for Internal Diseases Intermedica, Nis, Serbia; 5Clinical Center of Serbia, De-
partment of Cardiology, Belgrade, Serbia; 6The Department of Cardiology, Dedinje Cardio-
vascular Institute, Belgrade, Serbia; 7Innovation Center, University of Niš, Serbia; 8Health
Center Kladovo, Kladovo, Serbia

1. INTRODUCTION
Beta-blockers (BBs) are an important class of drugs, with numerous indications in cardiology, emergency and general
medicine. The indications include heart failure (HF), acute myocardial infarction (AMI), post-MI [1], supraventricular and ven-
tricular arrhythmias, chronic coronary syndrome, systemic arterial hypertension (HTN), hypertrophic cardiomyopathy and aor-
tic aneurysm or dissection. All BBs decrease heart rate (HR) and blood pressure (BP), the major determinants of myocardial
oxygen consumption; therefore, myocardial anti-ischemic action is a class effect. On the other hand, it is very important that not
all BBs decrease all-cause mortality and sudden death; therefore, their crucial characteristics are not the class effect [2].

2. LITERATURE OVERVIEW
Importantly, not all indications and contraindications are valid for each BB because there is only some degree of uniformity
among BBs as a class of drugs [3-5]. Despite their common mechanism of action, BBs show several distinctions regarding spe-
cific activities [6]. To start with the basic characteristic of BBs, the effect on HR is stronger for e.g. bisoprolol vs nebivolol (in
the average doses), while the opposite is true for the action on BP.
BBs differ in the degree of preferential affinity for β-adrenergic receptors (β-ARs) that is, in their β1 selectivity (cardiose-
lectivity), the degree of antagonist activity towards β-ARs, pharmacokinetic properties [7] (e.g. half-life, lipophilicity, excre-
tion), as well as additional pharmacodynamic properties e.g. vasodilating properties [8] (α-receptor blocking property or capa-
bility to stimulate nitric oxide production), intrinsic sympathomimetic activity (ISA), membrane stabilizing activities (MSA),
inverse agonist [9] and biased agonist activity [10] and evidence-based indication in HF [11].
These specific properties of BBs additionally determine not only their indications [12] but the distinctions in their side ef-
fects and contraindications [7]. Administration of an appropriate BB is of importance, according to the main indication (which
is supported by evidence and recommended in current guidelines), as well as according to patient’s co-morbidities as additional
indications [13]. For example, not all BBs have an acute myocardial infarction (AMI) as an evidence-based indication [14].
Moreover, only a few of numerous BBs are recommended for HF with reduced left ventricular ejection fraction (LVEF) [15,
16]. Furthermore, the effect of various BBs on central (aortic) BP is different: vasodilatory BBs (such as carvedilol and nebivo-
lol) decrease it, while the first and the second generation of BBs do not. Therefore, vasodilatory BBs (by decreasing aortic BP)
can be expected to better prevent aortic complications (dissection and aneurysm) in patients with Marfan syndrome [17].
Administration of an appropriate BB regarding the specific indication expectedly results in improvement of the patient’s
condition, which progresses to better adherence, and consequently reduces the chance for BB rebound [13]. Compelling indica-
tions for antihypertensives are listed in guidelines [18, 19] and they are very useful to help optimize antihypertensive treatment
[19-21].
Having in mind how many differences there are among BBs, it seems logical and practical not to refer to them always as a
group, but to individualize the choice for specific indications. The first suggestion is to improve the classification of BBs, by
incorporating indications for individual BB. For example, for bisoprolol, the numerous indications could include HF, AMI,
______________________________
*Address correspondence to this author at the Institute for Treatment and Rehabilitation Niska Banja, Serbia, Street: Srpskih junaka 2, 18205 Niska Banja,
Serbia; Tel: +381637710470; E-mail: milovanstojanovic1987@gmail.com

1570-1611/21 $65.00+.00 © 2021 Bentham Science Publishers

2 Current Vascular Pharmacology, 2021, Vol. 19, No. 00 Letter to the Editor

post-MI, chronic coronary syndrome, supraventricular and ventricular arrhythmias, HTN, aortic aneurysm or dissection, hyper-
trophic cardiomyopathy, etc. The second suggestion is to improve (some of) the current reports on a specific indication (dis-
ease) by listing exactly which BB is indicated. For example, for HF (both with and without preserved LVEF), only 3 BBs
(carvedilol, bisoprolol, metoprolol succinate) should be listed according to some guidelines [16] or 4 BBs (the 3 BBs already
mentioned plus nebivolol) as recommended by other guidelines [15]. The third suggestion is to explain how strong the evidence
is for each BB. For example, evidence-based indication (derived from several randomised clinical trials) for a particular BB can
be marked as the level of evidence A (LOE-A). Similarly, LOE-C can be used if the indication for another BB as suggested by
experts. The additional (fourth) suggestion is that in large tables with numerous drugs (such as compelling indications for anti-
hypertensive drugs) when BBs are mentioned, a couple of proper individual examples should be listed in parenthesis. This can
help prevent inadequate choices from the BB class (as BBs are very different).
Lists of compelling indications for BBs, or the other way round – list of diseases as indications for a particular BB can help
physicians to select the most appropriate BB. Namely, in a paper about tremor, in the part about treatment, instead of (or in ad-
dition to) BB, should list “propranolol” (which blocks strongly β2-ARs) and not e.g. bisoprolol (because it is a β1-selective BB
and therefore not indicated for tremor treatment). Similarly, if the topic is the chronic treatment of ventricular tachycardia in
patients with chronic obstructive lung disease, potential mistakes in practice can be avoided if “bisoprolol” is stated instead of
BB. Even a better example is the direct comparison between the first BB used (propranolol) and the latest one (nebivolol): pro-
pranolol is not β1-selective (“cardioselective”) and therefore is indicated for tremor, but not in chronic obstructive lung disease,
etc. while nebivolol is very cardioselective (and has a better metabolic profile as far as glycaemia and cholesterol are con-
cerned) [20]. Moreover, propranolol is not vasodilatory but nebivolol is; propranolol has membrane stabilizing activity, but
nebivolol does not [22]; propranolol is not indicated in congestive heart failure while nebivolol is recommended by the Euro-
pean Society of Cardiology (ESC) for heart failure, particularly with preserved ejection fraction (HFpEF) [15]. Indeed, such
tables with individual BBs and their compelling indications (with the levels of evidence) are very important and ought to be
created by international experts, in the form of position paper/guidelines. Table 1 illustrates the main proposal of the paper and
it may serve as a material to initiate this process.
Table 1. Characteristics of some currently used β-blockers.

Additional
β1-AR ISA Activity / Intensive First–
Lipophilicity Vasodilata- α-AR Block- Compelling Indications
NAME Specificity β3 Agonism pass Metabolism
[2, 28, 29] tion [30, 31] ade [32] [27, 33, 34]
[23, 24] [25-27] in the Liver [5]

Supraventricular tachyarrhythmias, Ven-

Bisoprolol High No Moderate No No No tricular tachyarrhythmias, HTN, chronic
coronary syndrome, heart failure, post-MI
HTN, stable angina, post-MI,
Metoprolol Supraventricular tachyarrhythmias, Ven-
Moderate- high No Moderate Yes No No
succinate tricular tachyarrhythmias,
Prevention of episodic migraine
HTN, stable angina, heart failure,
Post-MI,
Carvedilol No No Moderate/high Yes Yes Yes Supraventricular tachyarrhythmias, Ven-
tricular tachyarrhythmias,
Portal hypertensive bleeding (prophylaxis)
Nebivolol High β3 agonist Moderate Yes Yes No HTN, heart failure
Hyperthyroidism,
Supraventricular tachyarrhythmias, Ven-
tricular tachyarrhythmias,
Propranolol No No High Yes No No
Essential tremor, Anxiety,
Portal hypertensive bleeding (prophylaxis)
Prevention of episodic migraine
HTN, chronic coronary syndrome, post-MI,
Atenolol Moderate/high No Low No No No Supraventricular tachyarrhythmias, Ven-
tricular tachyarrhythmias
Abbreviations: intrinsic sympathomimetic activity (ISA); adrenergic receptor (AR); arterial hypertension (HTN); myocardial infarction (MI)

CONCLUSION
BBs differ within the class in so many ways that it is not only logical but also practical for real-life clinical practice that
experts in the field make a list of the compelling indications for individual BBs. The time has come to incorporate our knowl-
edge about BBs into a new approach of presenting these useful and very individual drugs.
Editorial Current Vascular Pharmacology, 2020, Vol. 18, No. 00 3

FUNDING
This work has been supported by the Serbian Ministry of Education and Science, Belgrade, Serbia, grant No.175092 and
grant No. III 41018

CONFLICT OF INTERESTS
This paper is neither submitted nor prepared for submission to another medical journal in part or as a whole. The authors
have no conflict of interest to declare regarding the present paper.

ACKNOWLEDGEMENTS
Declared none.

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